To determine the dose-limiting toxicity of TH-302 [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

TO determine the number of participants with Adverse Events as a measure of safety and tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To determine the efficacy of TH-302 via specific response criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:

40

Study Start Date:

June 2010

Study Completion Date:

August 2013

Primary Completion Date:

August 2013 (Final data collection date for primary outcome measure)

Intervention Details:

Drug: TH-302

TH-302 will be administered as a 30-minute intravenous infusion daily for 5 days every 21 days. Patients who successfully complete a 3-week treatment cycle without evidence of significant treatment-related toxicity or clinically significant progressive disease will continue to receive treatment for up to six cycles.

Detailed Description:

Tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy (Brown et al, 2004; Boyle 2006). TH-302, a hypoxia activated prodrug (HAP), exploits the hypoxic nature of tumors while having little or no effect on normal tissue. TH-302 belongs to a class of alkylating agents called oxazaphosphorines which have major experimental and clinical activity (Brock 1989). Since TH-302 is selectively targeted to the hypoxic microenvironment, this agent may represent an improvement over other agents in this class. Preclinical data support the hypothesis that TH-302 targets hypoxic regions of tumors and also is able to kill other tumor cells in normoxic regions as a result of cytotoxin diffusion, leading to significant effects on tumor growth. Preclinical data has shown that TH-302 has anti-tumor activity in multiple myeloma cells in vivo and in vitro.

Additional preclinical data demonstrated the marked expansion of the hypoxic bone marrow areas in diseased mice with ALL. These results suggest that this agent may be useful in treating advanced leukemias. The drug is stable in plasma and liver, does not appear to be at risk for drug-drug interactions, and has mild, reversible toxicities. In this dose-escalation study, patients with advanced leukemias will receive infusions of TH-302 to determine the maximum tolerated dose.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

At least 18 years of age.

Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's IRB/Ethics Committee.

Relapsed/refractory leukemias for which no standard therapy options are anticipated to result in a durable remission.

Acute myelogenous leukemia (AML) by WHO classification relapsed or refractory to standard chemotherapy; unsuitable for standard chemotherapy or unwilling to undergo standard chemotherapy.

Age > 60 years with AML not candidates for or have refused standard chemotherapy, excluding subjects with acute promyelocytic leukemia (APL) or with favorable cytogenetic abnormalities [inv16, t(8;21)].

ECOG performance status of less than or equal to 3

Adequate organ function as indicated by the following laboratory assessments performed within 14 days prior to the first dose of study drug:

Total bilirubin ≤ 1.5 times upper limit of normal (x ULN) (≤ 3 x ULN if due to leukemic involvement or Gilbert's syndrome).

All women of childbearing potential must have a negative serum pregnancy test and women and men subjects must agree to use effective means of contraception (surgical sterilization or the use or barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose

Exclusion Criteria:

New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within 6 months prior to Day 1, or unstable arrhythmia

Seizure disorders requiring anticonvulsant therapy

Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia

Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery

Active uncontrolled infection

Systemic chemotherapy (with the exception of hydroxyurea and/or steroids) within 14 days (or within 5 half-lives for an investigational agent) prior to first dose of study drug, unless there is evidence of rapidly progressive disease. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease is permitted.

Known active infection with HIV, hepatitis B, or hepatitis C

Patients who have exhibited allergic reactions to a similar structural compound, biological agent, or formulation (containing solutol and/or propylene glycol)

Females who are pregnant or breast-feeding

Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study

Unwillingness or inability to comply with the study protocol for any reason

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01149915